The overall objective of the proposed research is to determine the contribution of endogenous hypothalamic NPY in the hyperphagia in obesity prone species. During the career award, the candidate will learn: 1) neurophysiological techniques to record from the central nervous system of the anesthetized rat and, 2) how to apply physiological genomics to the study of ingestive behavior. This multidisciplinary training will advance the candidate's career goal to become an independent research scientist. Experiments will be conducted at the Bourne Laboratory (White Plains, NY) with Dr. Gary Schwartz, an expert in neurophysiological evaluation of sensory controls of food intake, as the primary mentor. Dr. Streamson Chua, Columbia University, will be a co-mentor, and he will provide training in physiological genomics and availability of transgenic leptin receptor rescues and inducible leptin receptor knock-out mutations. NPY has been proposed to increase feeding by increasing appetitive behaviors that precede and facilitate contact with food. Consistent with this hypothesis, we have shown that NPY dramatically increases instrumental responding for food in rats and mice. We also find that NPY only weakly stimulates instrumental responding when food is not available. These data suggest that signals arising from food stimuli are critical in NPY's ability to promote instrumental responding for food. In the proposed studies, we will perform behavioral and brainstem neurophysiological experiments designed to elucidate the neurochemical and genetic basis of hyperphagia in obesity prone rodents with leptin-signalling deficits. We will test the following 2 hypotheses: 1) Exogenous central NPY promotes instrumental responding for food by increasing the behavioral and neurophysiological potency of orosensory food stimuli, and, 2) Upregulation of endogenous hypothalamic NPY in hyperphagic genetic rodent models with leptin signalling deficits mediates increased instrumental responding to obtain food. We will evaluate instrumental responding for food after manipulating endogenous hypothalamic NPY levels in transgenic mouse models with leptin signalling deficits by: 1) replacing leptin, or 2) by altering the expression of leptin receptors. Results from these studies will help to reveal the contribution of endogenous hypothalamic NPY in the hyperphagia in obesity prone species.